The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: Clinical manifestations and long-term follow-up

Objective

To analyze the clinical manifestations and response to treatment in a cohort of adult patients presenting with recurrent inflammatory attacks and carrying low-penetrance TNFRSF1A variants, as well as to provide data on their long-term follow-up.

Methods

We performed a retrospective chart review of 36 patients carrying low-penetrance TNFRSF1A variants. Moreover, 60 genetically negative patients treated for recurrent inflammatory attacks and 13 patients with structural TNFRSF1A mutations were also analyzed. Detailed demographic and clinical data were collected at the time of molecular screening and at each follow-up visit. Treatments and markers of inflammation were also assessed.

Results

Individuals with low-penetrance TNFRSF1A variants have a lower family history for inflammatory attacks and present with a later disease onset compared with patients with structural mutations, but do not differ, in this respect, with genetically negative individuals. Moreover, low-penetrance variants are less frequently associated with a chronic disease course, with clinical manifestations such as abdominal pain and myalgia, and with amyloidosis. A distinctive clinical feature is a higher rate of pericarditis. Interestingly, mutation-negative patients were found to present with a significant history of recurrent pharyngitis during childhood. Patients with low-penetrance variants are mostly managed with short courses of steroids or non-steroidal anti-inflammatory drugs on attacks. Although the need for a biological treatment is significantly lower compared with patients with structural mutations, still approximately 20% of individuals with recurrent inflammatory attacks carrying low-penetrance variants ultimately require these therapies.

Conclusions

Our study confirms that low-penetrance TNFRSF1A variants can be associated with an autoinflammatory phenotype. Although a chronic disease course is rarely observed, some patients ultimately benefit from a biological treatment.     

On the origin of long-range correlations in texts

The complexity of human interactions with social and natural phenomena is mirrored in the way we describe our experiences through natural language. In order to retain and convey such a high dimensional information, the statistical properties of our linguistic output has to be highly correlated in time. An example are the robust observations, still largely not understood, of correlations on arbitrary long scales in literary texts. In this paper we explain how long-range correlations flow from highly structured linguistic levels down to the building blocks of a text (words, letters, etc..). By combining calculations and data analysis we show that correlations take form of a bursty sequence of events once we approach the semantically relevant topics of the text. The mechanisms we identify are fairly general and can be equally applied to other hierarchical settings.     

Effect of time to infusion of autologous stem cells (24 vs. 48 h) after high-dose melphalan in patients with multiple myeloma

High‐dose melphalan (HD‐Mel) is considered the current standard of care among the preparative regimens used in autologous peripheral blood stem cell transplantation (SCT) for multiple myeloma (MM), but optimal time and schedule of administration is not defined. We retrospectively analyzed outcomes and toxicities of HD‐Mel administered on day ‐2 vs. day ‐1 before autologous stem cells infusion. A total of 138 consecutive MM patients treated at Penn State Hershey Cancer Institute between 2007 and 2010 were included in this study. No difference in time to hematopoietic recovery, common SCT‐related toxicities, and clinical outcomes was seen between patients who received HD‐Mel on day ‐2 (group A, n = 47), and those who received it on day ‐1 (group B, n = 91). Prompt and full hematopoietic recovery occurred even when stem cells were infused between 8 and 24 h after completion of chemotherapy. In the absence of prospective and randomized data, we conclude that a single I.V. infusion of HD‐Mel on day ‐1 is a safe and effective practice, and the so‐called ‘day of rest’ before the transplant appears not to be necessary.     

Hepatic encephalopathy and health-related quality of life

The impact of overt hepatic encephalopathy on health-related quality of life is well defined, but it remains to be demonstrated how much the presence of minimal hepatic encephalopathy (MHE) might impair patients' perceived health status. MHE reduces cognitive abilities, with specific impairment in manual abilities, which can lead to a depressed mood that impairs perceived health status. Therefore, all subjects with cirrhosis should be systematically screened for MHE by validated tools. Early detection and treatment is mandatory to improve the quality of life of patients with advanced cirrhosis, their social isolation, and their daily lives.     

Are there advances in pharmacotherapy for panic disorder? A systematic review of the past five years

Introduction: Several effective medications are available for treating panic disorder (PD). However, outcomes are unsatisfactory in a number of patients, suggesting the usefulness of expanding the array of antipanic drugs and improving the quality of response to current recommended treatments.

Areas covered: The authors have performed an updated systematic review of pharmacological studies (phase III onwards) to examine whether advances have been made in the last five years. Only four studies were included. D-cycloserine no longer seemed promising as a cognitive-behavioral therapy (CBT) enhancer. Some preliminary findings concerning the optimization of recommended medications deserved consideration, including: the possibility that SSRIs are more effective than CBT alone in treating panic attacks, combined therapy is preferable when agoraphobia is present, and clonazepam is more potent than paroxetine in decreasing panic relapse.

Expert opinion: Given the lack of novel treatments, expanding a personalized approach to the existing medications seems to be the most feasible strategy to improve pharmacotherapy outcomes regarding PD. Recent technological progress, including wearable devices collecting real-time data, ‘big data’ platforms, and application of machine learning techniques might help make outcome prediction more reliable. Further research on previously promising novel treatments is also recommended.